Murine cytotoxic effector cells and their progenitors recognize membrane-bound viral and tumor antigens only in association with H-2 histocompatibility (H) antigens. In man an analogous HLA restriction of cytotoxic responses to trinitrophenol (TNP) and the Y-linked antigen has been described. Immune response genes in the mouse control the ability to recognize self, and there are examples of defective genes. Stains bearing these genes cannot generate cytotoxic responses to H-2 restricted antigens, not because they cannot recognize the antigen but because they cannot recognize self. Some humans may similarly be defective in their ability to recognize some of their own H antigens. It is possible that tumors escape immune survillance if their antigens become associated by selective survival with those H antigens which the host is unable to recognize for genetic reasons. It is proposed to test these hypotheses: some patients with cancer have a defect in their ability to recognize self; their tumor arose partly as a consequence of this defect; the defect is hereditary and linked to HLA. These hypotheses can be tested in families of cancer patients with the use of recently developed methods for in vitro sensitization of human peripheral blood lymphocytes in TNP-modified autologous lymphocytes and for assay of these cytotoxic cells on TNP-modified allogeneic targets with shared H antigens. The identification of such defects and the demonstration of a causal relation between the defect and the appearance of a tumor has important implications for the detection of cancer-prone individuals. Correction of the defect, as through the transplantation of responder lymphocytes, might then be a particularly effective form of specific cancer prophylaxis.